Abstract
BackgroundAlthough obesity and diabetes commonly co-exist, the evidence base to support obesity as the major driver of type 2 diabetes mellitus (T2DM), and the mechanisms by which this occurs, are now better appreciated.DiscussionThis review briefly examines several sources of evidence – epidemiological, genetic, molecular, and clinical trial – to support obesity being a causal risk factor for T2DM. It also summarises the ectopic fat hypothesis for this condition, and lists several pieces of evidence to support this concept, extending from rare conditions and drug effects to sex- and ethnicity-related differences in T2DM prevalence. Ectopic liver fat is the best-studied example of ectopic fat, but more research on pancreatic fat as a potential cause of β-cell dysfunction seems warranted. This ectopic fat concept, in turn, broadly fits with the observation that individuals of similar ages can develop diabetes at markedly different body mass indexes (BMIs). Those with risk factors leading to more rapid ectopic fat gain – for example, men (compared with women), certain ethnicities, and potentially those with a family history of diabetes, as well as others with genes linked to a reduced subcutaneous adiposity – are more likely to develop diabetes at a younger age and/or lower BMI than those without.SummaryObesity is the major risk factor for T2DM and appears to drive tissue insulin resistance in part via gain of ectopic fat, with the best-studied organ being the liver. However, ectopic fat in the pancreas may contribute to β-cell dysfunction. In line with this observation, rapid resolution of diabetes linked to a preferential and rapid reduction in liver fat has been noted with significant caloric reduction. Whether these observations can help develop better cost-effective and sustainable lifestyle /medical interventions in patients with T2DM requires further study.
Highlights
Obesity and diabetes commonly co-exist, the evidence base to support obesity as the major driver of type 2 diabetes mellitus (T2DM), and the mechanisms by which this occurs, are better appreciated
Summary In summary, it is clear that obesity is a major risk factor for T2DM, and appears to drive tissue insulin resistance via gain of ectopic fat, with the best-studied organ being the liver
It is clear that different individuals will start to expand their ectopic stores at different body mass indexes (BMIs) and levels of total adiposity, dependent upon their unmodifiable characteristics so that some groups, such as South Asian men with a family history of T2DM, have a very high diabetes risk even at modest BMIs
Summary
Obesity and diabetes commonly co-exist, the evidence base to support obesity as the major driver of type 2 diabetes mellitus (T2DM), and the mechanisms by which this occurs, are better appreciated. Obesity and type 2 diabetes mellitus (T2DM) commonly co-exist, the evidence to show that obesity is a cause of T2DM, and the mechanism by which it does so are only beginning to be fully appreciated. We discuss the range of evidence to support this view. We describe the concept of ectopic fat as an important mechanistic link between obesity and T2DM in many individuals
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